Sporadic Gastric Well-Differentiated Neuroendocrine Tumors Have a Higher Ki-67 Proliferative Index

Abstract

Well-differentiated neuroendocrine tumor (WDNET) of the stomach can arise in three distinct clinical settings: (1) in association with autoimmune atrophic gastritis, (2) in association with multiple neuroendocrine neoplasia type I (MEN I) or Zollinger-Ellison syndrome (ZES), or (3) sporadic. The Ki-67 proliferative index (PI) in gastric WDNETs in these three distinct clinical settings has not been evaluated in detail. Forty-five gastric WNETs underwent polypectomy (n=4), endoscopic mucosal resection (n=12), and surgical resection (n=29) between 1994 and 2015 were included. H&E slides from each case were reviewed, and Ki-67 immunostain was performed on one representative tumor block. Ki-67 PI was determined by quantitative Aperio image analysis software in areas of strongest nuclear labeling ("hot spots"), and correlated with underlying clinical and pathological features. Twenty-one patients were male and 24 female with a median age of 57years (range, 30-80years). Tumors were classified as type I (n=17), type II (n=6), and type III (n=22) WDNETs. Types II and III showed more advanced TNM stage compared to type I (p=0.02, overall). WHO grade based on Ki-67 PI was higher in type III WDNETs [grade 1 (G1), n=3; grade 2 (G2), n=15; and grade 3 (G3), n=4] than in type I WDNETs [G1, n=5; G2, n=12] and in type II WDNETs [G1, n=2; G2, n=4] (p=0.050, overall). Ki-67 PI was significantly higher in type III WDNETs (mean±SD=13.0±13.3%) than in non-sporadic (type I and II) WDNETs (mean±SD=5.3±3.3%; p=0.015). There was no difference in Ki-67 PI between type I WDNETs (mean±SD=5.2±3.5%) and type II WDNETs (mean±SD=5.6±3.1%; p=0.817). Higher Ki-67 PI was associated with higher tumor T stage (p=0.003) and also tended to be associated with lymph node metastasis (p=0.071). In the Kaplan-Meier survival analysis, type I was associated with a significantly longer disease-free survival (DFS) time compared to type II (p=0.018) or III (0.010). Also, the WHO G3 group had a significantly shorter DFS time than the WHO G1 (p=0.020) or G2 (p=0.007) group. Gastric WDNET is a heterogeneous disease entity encompassing three clinical subtypes-type I, type II, and type III-having their own distinct clinicopathologic characteristics and prognosis. Our results showed that sporadic (type III) WDNET had a significantly higher Ki-67 PI than non-sporadic cases (type I or II); increased PI was associated with higher tumor stage. We also described four type III cases of morphologically WD gastric NET with WHO grade 3 on the basis of Ki-67 PI.